文献类型：期刊文献

英文题名：Sulfated polysaccharides target RANK Lys97 to inhibit osteoclast differentiation and reverse osteoporosis

作者：Wang, Xiaogang[1,2];Ji, Luli[1,2];Yu, Yuanman[1,2];Yu, Jiaze[1,2];Wang, Jing[1,3];Liu, Changsheng[1,2,4]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Engn Res Ctr Biomed Mat, Minist Educ, Shanghai, Peoples R China;[3]East China Univ Sci & Technol, Key Lab Ultrafine Mat, Minist Educ, Shanghai, Peoples R China;[4]East China Univ Sci & Technol, Frontiers Sci Ctr Materiobiol & Dynam Chem, Shanghai, Peoples R China

年份：2026

外文期刊名：NATURE BIOMEDICAL ENGINEERING

收录：;EI(收录号：20263121226172);Scopus(收录号：2-s2.0-105046242784);WOS:【SCI-EXPANDED(收录号:WOS:001836091700001)】；

基金：This study was supported by the Basic Science Center Program (T2288102, C.L.), the Key Program of the National Natural Science Foundation of China (32230059, J.W.), the Foundation of Frontiers Science Center for Materiobiology and Dynamic Chemistry (JKVD1211002, C.L.), the National Natural Science Foundation of China (32401128, X.W.), the Postdoctoral Fellowship Program of CPSF (GZC20230793, X.W.) and Shanghai Postdoctoral Excellence Program (2023251, X.W.). Our micro-CT analysis of bone samples was conducted at the Shanghai Synchrotron Radiation Facility with the aid of H. Guo. Our FACS experiment was performed at the Optogenetics and Synthetic Biology Interdisciplinary Research Center with the aid of J. Lu. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

语种：英文

外文关键词：Polysaccharides - Sulfur compounds

摘要：Current osteoporosis treatments fail to balance bone resorption and formation. Here we show that engineered 2-N,6-O-sulfated chitosan (26SCS), a synthetic pentasaccharide, restores 115% bone mass (therapeutic) and prevents 66% bone loss, surpassing bisphosphonates by simultaneously suppressing osteoclastogenesis and promoting vascularized osteogenesis. Mechanistically, 26SCS targets K97 in receptor activator of nuclear factor-kappa B (RANK) through geometrically matched sulfate pairs, blocking RANK ligand (RANKL) signalling to arrest preosteoclast fusion while enhancing platelet-derived growth factor-BB (PDGF-BB) secretion via preserved preosteoclast viability to drive angiogenesis-coupled mineralization. Structural and functional analyses reveal that carboxyl groups in natural glycosaminoglycans such as heparin competitively bind K97, disrupting therapeutic specificity-a limitation overcome by 26SCS's carboxyl-free design and sequence-controlled sulfation. Unlike monosulfated analogues (2SCS/6SCS) that oversuppress osteoclastogenesis or lack pro-osteogenic effects, 26SCS's dual sulfation balances inhibition with trophic support. Thus, this work redefines glycosaminoglycan therapeutics via sulfation-patterned, topology-engineered biomaterials harmonizing bone metabolism.